: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of antibodies to DNA (anti-DNA). These antibodies serve as markers of diagnostic and prognostic significance. As a model to elucidate the mechanism of this response, Dr. Pisetsky's laboratory has studied the effects of immunization of normal and autoimmune mice with bacterial DNA. This DNA is a potent immunogen because of its content of CpG motifs that stimulate B cell activation and cytokine production. In normal mice, bacterial DNA can induce antibodies specific for the immunizing DNA while in autoimmune NZB/NZW mice, immunization leads to the production of autoantibodies with properties of SLE anti-DNA. Immunized NZB/NZW mice, however, fail to develop renal disease, possibly related to cytokine effects. To analyze further this model, 3 specific aims are proposed: 1) To investigate the genetic basis of induced anti-DNA production through study of a variety of inbred and congenic strains immunized with bacterial DNA; 2) To investigate the ability of mammalian DNA to inhibit immune responses elicited by bacterial DNA and other immune stimulants; and 3) To assess mechanisms by which bacterial DNA can stimulate cellular responses, focusing on the basis of DNA binding and uptake. The responses of mice deficient in the Type A macrophage scavenger receptor, a putative DNA receptor, will be assessed. Together, these studies will clarify important steps by which foreign DNA antigen can modulate the course of autoimmunity.